Abstract
The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be ‘rejuvenated’ by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging stem cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY . (2007). Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev 21: 3244–3257.
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J et al. (2009). The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23: 1171–1176.
Ahlenius H, Visan V, Kokaia M, Lindvall O, Kokaia Z . (2009). Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain. J Neurosci 29: 4408–4419.
Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G et al. (2009). Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12: 95–104.
Anthony TE, Klein C, Fishell G, Heintz N . (2004). Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron 41: 881–890.
Arantes-Oliveira N, Apfeld J, Dillin A, Kenyon C . (2002). Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science 295: 502–505.
Attema JL, Pronk CJ, Norddahl GL, Nygren JM, Bryder D . (2009). Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence. Oncogene 28: 2238–2243.
Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L et al. (2008). SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8: 333–341.
Barker N, Hurlstone A, Musisi H, Miles A, Bienz M, Clevers H . (2001). The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J 20: 4935–4943.
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003–1007.
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M et al. (2009). Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 23: 1177–1182.
Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B . (1992). Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci USA 89: 2804–2808.
Beckervordersandforth R, Tripathi P, Ninkovic J, Bayam E, Lepier A, Stempfhuber B et al. (2010). In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell 7: 744–758.
Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D et al. (2010a). Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci USA 107: 5465–5470.
Beerman I, Maloney WJ, Weissmann IL, Rossi DJ . (2010b). Stem cells and the aging hematopoietic system. Curr Opin Immunol 22: 500–506.
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763–776.
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A . (2009). An operational definition of epigenetics. Genes Dev 23: 781–783.
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J et al. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125: 315–326.
Biteau B, Hochmuth CE, Jasper H . (2008). JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3: 442–455.
Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H . (2010). Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet 6: e1001159.
Blanpain C, Horsley V, Fuchs E . (2007). Epithelial stem cells: turning over new leaves. Cell 128: 445–458.
Blasco MA . (2007). The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8: 299–309.
Bockhold KJ, Rosenblatt JD, Partridge TA . (1998). Aging normal and dystrophic mouse muscle: analysis of myogenicity in cultures of living single fibers. Muscle Nerve 21: 173–183.
Bondolfi L, Ermini F, Long JM, Ingram DK, Jucker M . (2004). Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiol Aging 25: 333–340.
Bonnet D, Dick JE . (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737.
Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M, Schmitt CA . (2007). FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21: 2775–2787.
Boyle M, Wong C, Rocha M, Jones DL . (2007). Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1: 470–478.
Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C et al. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317: 807–810.
Brack AS, Murphy-Seiler F, Hanifi J, Deka J, Eyckerman S, Keller C et al. (2009). BCL9 is an essential component of canonical Wnt signaling that mediates the differentiation of myogenic progenitors during muscle regeneration. Dev Biol 335: 93–105.
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C et al. (2007). The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21: 525–530.
Breton-Provencher V, Lemasson M, Peralta III MR, Saghatelyan A . (2009). Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors. J Neurosci 29: 15245–15257.
Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J et al. (2007). Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12: 328–341.
Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, Tanger E et al. (2005). Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 19: 1438–1443.
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015.
Bug G, Gul H, Schwarz K, Pfeifer H, Kampfmann M, Zheng X et al. (2005). Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells. Cancer Res 65: 2537–2541.
Buszczak M, Spradling AC . (2006). Searching chromatin for stem cell identity. Cell 125: 233–236.
Cameron HA, McKay RD . (1999). Restoring production of hippocampal neurons in old age. Nat Neurosci 2: 894–897.
Carlson ME, Conboy IM . (2007). Loss of stem cell regenerative capacity within aged niches. Aging Cell 6: 371–382.
Carlson ME, Hsu M, Conboy IM . (2008). Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 454: 528–532.
Carlson ME, Suetta C, Conboy MJ, Aagaard P, Mackey A, Kjaer M et al. (2009). Molecular aging and rejuvenation of human muscle stem cells. EMBO Mol Med 1: 381–391.
Cavalli G, Paro R . (1998). The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93: 505–518.
Challen GA, Boles NC, Chambers SM, Goodell MA . (2010). Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell 6: 265–278.
Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA . (2007). Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5: e201.
Chen J, Luo Q, Yuan Y, Huang X, Cai W, Li C et al. (2010). Pygo2 associates with MLL2 histone methyltransferase (HMT) and GCN5 histone acetyltransferase (HAT) complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion. Mol Cell Biol 30: 5621–5635.
Chen S, Whetstine JR, Ghosh S, Hanover JA, Gali RR, Grosu P et al. (2009). The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span. Proc Natl Acad Sci USA 106: 1496–1501.
Cheshier SH, Morrison SJ, Liao X, Weissman IL . (1999). In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA 96: 3120–3125.
Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z et al. (2010). Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci USA 107: 8824–8829.
Cho RH, Sieburg HB, Muller-Sieburg CE . (2008). A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 111: 5553–5561.
Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W et al. (2008). TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet 4: e10.
Chuikov S, Levi BP, Smith ML, Morrison SJ . (2010). Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol 12: 999–1006.
Clelland CD, Choi M, Romberg C, Clemenson Jr GD, Fragniere A, Tyers P et al. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325: 210–213.
Conboy IM, Conboy MJ, Smythe GM, Rando TA . (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science 302: 1575–1577.
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA . (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433: 760–764.
Conboy IM, Rando TA . (2005). Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4: 407–410.
Corbu A, Scaramozza A, Badiali-DeGiorgi L, Tarantino L, Papa V, Rinaldi R et al. (2010). Satellite cell characterization from aging human muscle. Neurol Res 32: 63–72.
Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . (2003). Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17: 3029–3035.
Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315: 1243–1249.
Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M et al. (2004). Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 101: 10042–10047.
Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A et al. (2009). Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459: 802–807.
de Haan G, Nijhof W, Van Zant G . (1997). Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood 89: 1543–1550.
de Haan G, Van Zant G . (1999). Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood 93: 3294–3301.
Deka J, Wiedemann N, Anderle P, Murphy-Seiler F, Bultinck J, Eyckerman S et al. (2010). Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Res 70: 6619–6628.
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A . (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703–716.
Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al. (2003). in vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17: 1253–1270.
Dumble M, Moore L, Chambers SM, Geiger H, Van Zant G, Goodell MA et al. (2007). The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood 109: 1736–1742.
Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K et al. (2007). Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1: 218–229.
Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S . (2004). Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24: 8354–8365.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al. (1998). Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317.
Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC . (2005). Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308: 1181–1184.
Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S . (2007). shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1: 87–99.
Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC et al. (2008). Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 8: 347–358.
Fiedler M, Sanchez-Barrena MJ, Nekrasov M, Mieszczanek J, Rybin V, Muller J et al. (2008). Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex. Mol Cell 30: 507–518.
Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S et al. (2009). Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106: 2700–2705.
Flores I, Cayuela ML, Blasco MA . (2005). Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309: 1253–1256.
Frescas D, Valenti L, Accili D . (2005). Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280: 20589–20595.
Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T . (2003). The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278: 4035–4040.
Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J . (1998). Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 36: 249–266.
Gheusi G, Cremer H, McLean H, Chazal G, Vincent JD, Lledo PM . (2000). Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci USA 97: 1823–1828.
Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L . (2004). Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305: 361.
Gibson MC, Schultz E . (1983). Age-related differences in absolute numbers of skeletal muscle satellite cells. Muscle Nerve 6: 574–580.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1: 555–567.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183: 1797–1806.
Goodman RH, Smolik S . (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev 14: 1553–1577.
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ . (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2: 260–265.
Greer EL, Brunet A . (2005). FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24: 7410–7425.
Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS et al. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466: 383–387.
Grewal SI, Klar AJ . (1996). Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86: 95–101.
Gu B, Sun P, Yuan Y, Moraes RC, Li A, Teng A et al. (2009). Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation. J Cell Biol 185: 811–826.
Guerrettaz LM, Johnson SA, Cambier JC . (2008). Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging. Proc Natl Acad Sci USA 105: 11898–11902.
Haigis MC, Guarente LP . (2006). Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 20: 2913–2921.
Hatta M, Cirillo LA . (2007). Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J Biol Chem 282: 35583–35593.
Hattiangady B, Shetty AK . (2008). Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29: 129–147.
Hayden MS, Ghosh S . (2008). Shared principles in NF-kappaB signaling. Cell 132: 344–362.
Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R . (2000). The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J 19: 1839–1850.
Hennighausen L, Robinson GW . (2005). Information networks in the mammary gland. Nat Rev Mol Cell Biol 6: 715–725.
Hirabayashi Y, Suzki N, Tsuboi M, Endo TA, Toyoda T, Shinga J et al. (2009). Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63: 600–613.
Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S et al. (2008). Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci USA 105: 15599–15604.
Ho L, Crabtree GR . (2010). Chromatin remodelling during development. Nature 463: 474–484.
Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A et al. (2009). An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci USA 106: 5181–5186.
Holland EC, Li Y, Celestino J, Dai C, Schaefer L, Sawaya RA et al. (2000). Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol 157: 1031–1037.
Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH . (2004). Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci USA 101: 16659–16664.
Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY et al. (2004). IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117: 225–237.
Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M . (2004). Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429: 562–566.
Imai S, Armstrong CM, Kaeberlein M, Guarente L . (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800.
Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M et al. (2008). Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11: 1153–1161.
Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H et al. (2004). Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21: 843–851.
Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S et al. (2006). PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51: 187–199.
Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M . (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164–168.
Jaenisch R, Bird A . (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 (Suppl): 245–254.
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM et al. (2006). Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443: 421–426.
Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC et al. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469: 102–106.
Jawerka M, Colak D, Dimou L, Spiller C, Lagger S, Montgomery RL et al. (2010). The specific role of histone deacetylase 2 in adult neurogenesis. Neuron Glia Biol 6: 93–107.
Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK et al. (2007). SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450: 415–419.
Jones DL . (2007). Aging and the germ line: where mortality and immortality meet. Stem Cell Rev 3: 192–200.
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N et al. (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19: 187–191.
Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P . (2007). Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1: 324–337.
Kaeberlein M, McVey M, Guarente L . (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13: 2570–2580.
Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E et al. (2006). The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107: 2170–2179.
Kamminga LM, van Os R, Ausema A, Noach EJ, Weersing E, Dontje B et al. (2005). Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells 23: 82–92.
Kaplan MS, Bell DH . (1984). Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J Neurosci 4: 1429–1441.
Katsumoto T, Aikawa Y, Iwama A, Ueda S, Ichikawa H, Ochiya T et al. (2006). MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev 20: 1321–1330.
Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M et al. (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136: 62–74.
Kawakami K, Nakamura A, Ishigami A, Goto S, Takahashi R . (2009). Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10: 415–421.
Kee N, Teixeira CM, Wang AH, Frankland PW . (2007). Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10: 355–362.
Kempermann G, Brandon EP, Gage FH . (1998a). Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr Biol 8: 939–942.
Kempermann G, Gast D, Gage FH . (2002). Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 52: 135–143.
Kempermann G, Kuhn HG, Gage FH . (1998b). Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18: 3206–3212.
Ketel CS, Andersen EF, Vargas ML, Suh J, Strome S, Simon JA . (2005). Subunit contributions to histone methyltransferase activities of fly and worm polycomb group complexes. Mol Cell Biol 25: 6857–6868.
Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A et al. (2010). Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab 12: 224–236.
Kim M, Moon HB, Spangrude GJ . (2003). Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 996: 195–208.
Kordon EC, Smith GH . (1998). An entire functional mammary gland may comprise the progeny from a single cell. Development 125: 1921–1930.
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L et al. (2004). Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114: 1299–1307.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 818–822.
Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G . (2006). Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging 27: 1505–1513.
Kuhn HG, Dickinson-Anson H, Gage FH . (1996). Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16: 2027–2033.
Kukekov VG, Laywell ED, Suslov O, Davies K, Scheffler B, Thomas LB et al. (1999). Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol 156: 333–344.
Kung AL, Rebel VI, Bronson RT, Ch'ng LE, Sieff CA, Livingston DM et al. (2000). Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev 14: 272–277.
Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D . (2002). Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16: 2893–2905.
Lagace DC, Whitman MC, Noonan MA, Ables JL, DeCarolis NA, Arguello AA et al. (2007). Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci 27: 12623–12629.
Lee CK, Weindruch R, Prolla TA . (2000). Gene-expression profile of the ageing brain in mice. Nat Genet 25: 294–297.
Lee KK, Workman JL . (2007). Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol 8: 284–295.
Lessard J, Sauvageau G . (2003). Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423: 255–260.
Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT et al. (2007). An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55: 201–215.
Lewis PD . (1968). Mitotic activity in the primate subependymal layer and the genesis of gliomas. Nature 217: 974–975.
Li J, Ebata A, Dong Y, Rizki G, Iwata T, Lee SS . (2008). Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol 6: e233.
Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY et al. (2009). Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18: 4897–4904.
Liang Y, Van Zant G, Szilvassy SJ . (2005). Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106: 1479–1487.
Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR . (2001). Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107: 603–613.
Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S et al. (2007). Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9: 424–429.
Lim DA, Huang YC, Swigut T, Mirick AL, Garcia-Verdugo JM, Wysocka J et al. (2009). Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458: 529–533.
Lin K, Dorman JB, Rodan A, Kenyon C . (1997). Daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278: 1319–1322.
Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J et al. (2007). Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317: 803–806.
Liu HK, Belz T, Bock D, Takacs A, Wu H, Lichter P et al. (2008). The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone. Genes Dev 22: 2473–2478.
Liu HK, Wang Y, Belz T, Bock D, Takacs A, Radlwimmer B et al. (2010). The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation. Genes Dev 24: 683–695.
Liu J, Cao L, Chen J, Song S, Lee IH, Quijano C et al. (2009). Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459: 387–392.
Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW et al. (2006). Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66: 6063–6071.
Lois C, Alvarez-Buylla A . (1993). Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 90: 2074–2077.
Longo VD, Kennedy BK . (2006). Sirtuins in aging and age-related disease. Cell 126: 257–268.
Lowe SW, Sherr CJ . (2003). Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 13: 77–83.
Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M et al. (2010). Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6: 445–456.
Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N et al. (2009). Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323: 1074–1077.
Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H . (2010). Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 13: 1338–1344.
Major MB, Roberts BS, Berndt JD, Marine S, Anastas J, Chung N et al. (2008). New regulators of Wnt/beta-catenin signaling revealed by integrative molecular screening. Sci Signal 1: ra12.
Martin C, Zhang Y . (2007). Mechanisms of epigenetic inheritance. Curr Opin Cell Biol 19: 266–272.
Maslov AY, Barone TA, Plunkett RJ, Pruitt SC . (2004). Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24: 1726–1733.
Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A . (2005). Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA 102: 11278–11283.
McMahon KA, Hiew SY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ et al. (2007). Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1: 338–345.
Merkle FT, Mirzadeh Z, Alvarez-Buylla A . (2007). Mosaic organization of neural stem cells in the adult brain. Science 317: 381–384.
Merson TD, Dixon MP, Collin C, Rietze RL, Bartlett PF, Thomas T et al. (2006). The transcriptional coactivator Querkopf controls adult neurogenesis. J Neurosci 26: 11359–11370.
Michallet M, Philip T, Philip I, Godinot H, Sebban C, Salles G et al. (2000). Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution. Exp Hematol 28: 858–870.
Michan S, Sinclair D . (2007). Sirtuins in mammals: insights into their biological function. Biochem J 404: 1–13.
Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M et al. (2008). SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452: 492–496.
Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S et al. (2007). Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1: 101–112.
Miyamoto K, Miyamoto T, Kato R, Yoshimura A, Motoyama N, Suda T . (2008). FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112: 4485–4493.
Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R . (2005). Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19: 1432–1437.
Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ . (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425: 962–967.
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J et al. (2006). Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443: 448–452.
Monaghan AP, Grau E, Bock D, Schutz G . (1995). The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. Development 121: 839–853.
Monje ML, Toda H, Palmer TD . (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science 302: 1760–1765.
Morgan DE, Crittenden SL, Kimble J . (2010). The C. elegans adult male germline: stem cells and sexual dimorphism. Dev Biol 346: 204–214.
Morgan JE, Partridge TA . (2003). Muscle satellite cells. Int J Biochem Cell Biol 35: 1151–1156.
Morita Y, Ema H, Nakauchi H . (2010). Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med 207: 1173–1182.
Morrison SJ, Spradling AC . (2008). Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132: 598–611.
Morrison SJ, Uchida N, Weissman IL . (1995). The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11: 35–71.
Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL . (1996). The aging of hematopoietic stem cells. Nat Med 2: 1011–1016.
Morrison SJ, Weissman IL . (1994). The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1: 661–673.
Morshead CM, Craig CG, van der Kooy D . (1998). in vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125: 2251–2261.
Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D et al. (1994). Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13: 1071–1082.
Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L et al. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124: 315–329.
Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W et al. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551–563.
Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B et al. (2002). Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111: 197–208.
Musaro A, Giacinti C, Borsellino G, Dobrowolny G, Pelosi L, Cairns L et al. (2004). Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. Proc Natl Acad Sci USA 101: 1206–1210.
Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y et al. (2010). TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463: 676–680.
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al. (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393: 386–389.
Narala SR, Allsopp RC, Wells TB, Zhang G, Prasad P, Coussens MJ et al. (2008). SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. Mol Biol Cell 19: 1210–1219.
Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn SA, Myers MP et al. (2006). A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126: 503–514.
Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C et al. (2007). DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447: 686–690.
Nishimura EK, Granter SR, Fisher DE . (2005). Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307: 720–724.
Nishino J, Kim I, Chada K, Morrison SJ . (2008). Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135: 227–239.
Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK et al. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135: 907–918.
Ogawa T, Kitagawa M, Hirokawa K . (2000). Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Ageing Dev 117: 57–68.
Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA et al. (1997). The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994–999.
Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y . (1996). The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87: 953–959.
Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H . (2006). Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 203: 2247–2253.
Oguro H, Yuan J, Ichikawa H, Ikawa T, Yamazaki S, Kawamoto H et al. (2010). Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell 6: 279–286.
Oh YH, Conard RA . (1972). Effect of aging on histone acetylation of the normal and regenerating rat liver. Life Sci II 11: 1207–1214.
Osawa M, Hanada K, Hamada H, Nakauchi H . (1996). Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273: 242–245.
Ou X, Chae HD, Wang RH, Shelley WC, Cooper S, Taylor T et al. (2010). SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse. Blood 117: 440–450.
Paik JH, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS et al. (2009). FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5: 540–553.
Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z et al. (2007). FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128: 309–323.
Palmer TD, Takahashi J, Gage FH . (1997). The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8: 389–404.
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH . (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17: 3727–3738.
Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL et al. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423: 302–305.
Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M et al. (2009). Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460: 66–72.
Pastrana E, Cheng LC, Doetsch F . (2009). Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc Natl Acad Sci USA 106: 6387–6392.
Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J et al. (2009). Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8: 460–472.
Pearce DJ, Anjos-Afonso F, Ridler CM, Eddaoudi A, Bonnet D . (2007). Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging. Stem Cells 25: 828–835.
Peinado MA, Quesada A, Pedrosa JA, Torres MI, Martinez M, Esteban FJ et al. (1998). Quantitative and ultrastructural changes in glia and pericytes in the parietal cortex of the aging rat. Microsc Res Technol 43: 34–42.
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328: 753–756.
Perez-Campo FM, Borrow J, Kouskoff V, Lacaud G . (2009). The histone acetyl transferase activity of monocytic leukemia zinc finger is critical for the proliferation of hematopoietic precursors. Blood 113: 4866–4874.
Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, Ninnemann O et al. (2008). Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10: 385–394.
Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R et al. (2010). SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12: 78–87.
Rando TA . (2005). The adult muscle stem cell comes of age. Nat Med 11: 829–831.
Rando TA . (2006). Stem cells, ageing and the quest for immortality. Nature 441: 1080–1086.
Rastelli L, Chan CS, Pirrotta V . (1993). Related chromosome binding sites for zeste, suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on enhancer of zeste function. EMBO J 12: 1513–1522.
Rebel VI, Kung AL, Tanner EA, Yang H, Bronson RT, Livingston DM . (2002). Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci USA 99: 14789–14794.
Renault V, Thornell LE, Eriksson PO, Butler-Browne G, Mouly V . (2002). Regenerative potential of human skeletal muscle during aging. Aging Cell 1: 132–139.
Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE et al. (2009). FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5: 527–539.
Reya T, Clevers H . (2005). Wnt signalling in stem cells and cancer. Nature 434: 843–850.
Rietze RL, Valcanis H, Brooker GF, Thomas T, Voss AK, Bartlett PF . (2001). Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412: 736–739.
Rine J, Strathern JN, Hicks JB, Herskowitz I . (1979). A suppressor of mating-type locus mutations in Saccharomyces cerevisiae: evidence for and identification of cryptic mating-type loci. Genetics 93: 877–901.
Ringrose L, Paro R . (2007). Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 134: 223–232.
Rogina B, Helfand SL . (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 101: 15998–16003.
Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL . (2007a). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447: 725–729.
Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ et al. (2005). Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA 102: 9194–9199.
Rossi DJ, Jamieson CH, Weissman IL . (2008). Stems cells and the pathways to aging and cancer. Cell 132: 681–696.
Rossi DJ, Seita J, Czechowicz A, Bhattacharya D, Bryder D, Weissman IL . (2007b). Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle 6: 2371–2376.
Roy K, Kuznicki K, Wu Q, Sun Z, Bock D, Schutz G et al. (2004). The Tlx gene regulates the timing of neurogenesis in the cortex. J Neurosci 24: 8333–8345.
Roy NS, Benraiss A, Wang S, Fraser RA, Goodman R, Couldwell WT et al. (2000). Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res 59: 321–331.
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C et al. (1999). Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701–712.
Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM . (2008). Self-renewal and expansion of single transplanted muscle stem cells. Nature 456: 502–506.
Sahin E, Depinho RA . (2010). Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464: 520–528.
Sanai N, Alvarez-Buylla A, Berger MS . (2005). Neural stem cells and the origin of gliomas. N Engl J Med 353: 811–822.
Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S et al. (2004). Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427: 740–744.
Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E et al. (2005). Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436: 1048–1052.
Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG et al. (2006). Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol 7: 1037–1047.
Schultz E, Gibson MC, Champion T . (1978). Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study. J Exp Zool 206: 451–456.
Schultz E, Lipton BH . (1982). Skeletal muscle satellite cells: changes in proliferation potential as a function of age. Mech Ageing Dev 20: 377–383.
Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA . (2010). DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463: 563–567.
Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA . (2008). Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev 22: 1865–1870.
Sgarra R, Furlan C, Zammitti S, Lo Sardo A, Maurizio E, Di Bernardo J et al. (2008). Interaction proteomics of the HMGA chromatin architectural factors. Proteomics 8: 4721–4732.
Sgarra R, Tessari MA, Di Bernardo J, Rustighi A, Zago P, Liberatori S et al. (2005). Discovering high mobility group A molecular partners in tumour cells. Proteomics 5: 1494–1506.
Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML et al. (2006). Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88.
Sharpless NE, DePinho RA . (2007). How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8: 703–713.
Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ et al. (2008). Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11: 1024–1034.
Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT et al. (2004). Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427: 78–83.
Shi Y . (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8: 829–833.
Shizuru JA, Negrin RS, Weissman IL . (2005). Hematopoietic stem and progenitor cells: clinical and preclinical regeneration of the hematolymphoid system. Annu Rev Med 56: 509–538.
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E . (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372–376.
Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ . (2010). Polycomb repressive complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci USA 107: 169–174.
Siebzehnrubl FA, Buslei R, Eyupoglu IY, Seufert S, Hahnen E, Blumcke I . (2007). Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells. Exp Brain Res 176: 672–678.
Song HJ, Stevens CF, Gage FH . (2002). Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 5: 438–445.
Song Z, Ju Z, Rudolph KL . (2009). Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status. Exp Gerontol 44: 75–82.
Spangrude GJ, Heimfeld S, Weissman IL . (1988). Purification and characterization of mouse hematopoietic stem cells. Science 241: 58–62.
Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D et al. (2006). Purification and unique properties of mammary epithelial stem cells. Nature 439: 993–997.
Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT et al. (2003). Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol 4: 124–131.
Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL et al. (2009). TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell 5: 64–75.
Sudo K, Ema H, Morita Y, Nakauchi H . (2000). Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192: 1273–1280.
Sun G, Alzayady K, Stewart R, Ye P, Yang S, Li W et al. (2010). Histone demethylase LSD1 regulates neural stem cell proliferation. Mol Cell Biol 30: 1997–2005.
Sun G, Yu RT, Evans RM, Shi Y . (2007). Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc Natl Acad Sci USA 104: 15282–15287.
Taraldsrud E, Grogaard HK, Solheim S, Lunde K, Floisand Y, Arnesen H et al. (2009). Age and stress related phenotypical changes in bone marrow CD34+ cells. Scand J Clin Lab Invest 69: 79–84.
Thomas T, Corcoran LM, Gugasyan R, Dixon MP, Brodnicki T, Nutt SL et al. (2006). Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev 20: 1175–1186.
Thomas T, Voss AK, Chowdhury K, Gruss P . (2000). Querkopf, a MYST family histone acetyltransferase, is required for normal cerebral cortex development. Development 127: 2537–2548.
Tissenbaum HA, Guarente L . (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410: 227–230.
Tothova Z, Gilliland DG . (2007). FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1: 140–152.
Tropepe V, Craig CG, Morshead CM, van der Kooy D . (1997). Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci 17: 7850–7859.
Trowbridge JJ, Snow JW, Kim J, Orkin SH . (2009). DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5: 442–449.
Trowbridge JJ, Orkin SH . (2010). DNA methylation in adult stem cells: new insights into self-renewal. Epigenetics 5: 189–193.
Uchida N, Tsukamoto A, He D, Friera AM, Scollay R, Weissman IL . (1998). High doses of purified stem cells cause early hematopoietic recovery in syngeneic and allogeneic hosts. J Clin Invest 101: 961–966.
Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M . (2004). Stem cells and cancer; the polycomb connection. Cell 118: 409–418.
van der Flier LG, Clevers H . (2009). Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71: 241–260.
van der Heide LP, Smidt MP . (2005). Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem Sci 30: 81–86.
van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM . (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 279: 28873–28879.
van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H et al. (1994). Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 8: 757–769.
Vaquero A, Loyola A, Reinberg D . (2003). The constantly changing face of chromatin. Sci Aging Knowledge Environ 2003: RE4.
Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D . (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16: 93–105.
Vick NA, Lin MJ, Bigner DD . (1977). The role of the subependymal plate in glial tumorigenesis. Acta Neuropathol 40: 63–71.
Vidanes GM, Bonilla CY, Toczyski DP . (2005). Complicated tails: histone modifications and the DNA damage response. Cell 121: 973–976.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C et al. (2006). The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439: 871–874.
Visvader JE . (2009). Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23: 2563–2577.
Voog J, Jones DL . (2010). Stem cells and the niche: a dynamic duo. Cell Stem Cell 6: 103–115.
Wagers AJ, Christensen JL, Weissman IL . (2002). Cell fate determination from stem cells. Gene Ther 9: 606–612.
Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS et al. (2004). Role of histone H2A ubiquitination in Polycomb silencing. Nature 431: 873–878.
Waterstrat A, Oakley E, Miller A, Swiderski C, Liang Y, Van Zant G . (2008) In: Rudolph KL (ed). Telomeres and Telomerase in Ageing, Disease, and Cancer. Springer: Berlin-Heidelberg, 111–140.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M . et al. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430: 686–689.
Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K et al. (2010). Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329: 444–448.
Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, Wang L et al. (2006). Increased hematopoietic stem cell mobilization in aged mice. Blood 108: 2190–2197.
Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinkovic D, Vercherat C et al. (2008). Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem 283: 25692–25705.
Yang XJ, Seto E . (2007). HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26: 5310–5318.
Zammit PS, Heslop L, Hudon V, Rosenblatt JD, Tajbakhsh S, Buckingham ME et al. (2002). Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate skeletal muscle fibers. Exp Cell Res 281: 39–49.
Zencak D, Lingbeek M, Kostic C, Tekaya M, Tanger E, Hornfeld D et al. (2005). Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci 25: 5774–5783.
Zhang CL, Zou Y, He W, Gage FH, Evans RM . (2008). A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451: 1004–1007.
Zhang R, Zhang Z, Zhang C, Zhang L, Robin A, Wang Y et al. (2004). Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat. J Neurosci 24: 5810–5815.
Zhao C, Deng W, Gage FH . (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132: 645–660.
Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K et al. (2003). Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA 100: 6777–6782.
Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD et al. (2010). The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140: 280–293.
Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP et al. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8: 119–130.
Zindy F, Quelle DE, Roussel MF, Sherr CJ . (1997). Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15: 203–211.
Acknowledgements
We thank Eric L Greer and Wendy W Pang for critical reading of the manuscript and helpful suggestions. This work was supported by a California Institute of Regenerative Medicine New Faculty Award (AB), an Ellison Medical Foundation Senior Award (AB) and an NSF graduate fellowship (EAP).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Pollina, E., Brunet, A. Epigenetic regulation of aging stem cells. Oncogene 30, 3105–3126 (2011). https://doi.org/10.1038/onc.2011.45
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2011.45
Keywords
This article is cited by
-
Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling
Inflammation and Regeneration (2023)
-
Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance
Nature Communications (2023)
-
Characterization and comparative DNA methylation profiling of four adipogenic genes in adipose-derived stem cells and dedifferentiated fat cells from aging subjects
Human Cell (2020)
-
Convergent adaptation of cellular machineries in the evolution of large body masses and long life spans
Biogerontology (2017)
